Stable HLA antibodies following sustained CD19+ cell depletion implicate a long-lived plasma cell source

Zhang, Zheng; Schuster, Stephen J.; Lacey, Simon F.; Milone, Michael C.; Monos, Dimitri; Bhoj, Vijay

doi:10.1182/bloodadvances.2020002435

Cited by 11 publications

(7 citation statements)

References 25 publications

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“…To determine whether HLA allo‐antibodies can also be maintained by CD19 ‐ PCs, we screened CART19‐treated patients who experienced sustained CD19 + cell aplasia for pre‐existing HLA antibodies and identified only one subject who had HLA allo‐antibodies prior to undergoing CAR T‐cell therapy. Despite continued CD19 + cell aplasia 2‐year post‐CAR T infusion, the HLA allo‐antibodies remained stable 56 . This result, albeit in one patient, is consistent with the lack of efficacy of rituximab at eradicating established allo‐antibodies, both pointing to a CD19 ‐ LLPC source.…”

Section: Car T Cells Targeting Cd19supporting

confidence: 65%

On the road to eliminating long‐lived plasma cells—“are we there yet?”

Markmann

Bhoj

2021

Immunological Reviews

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Central to protective humoral immunity is the activation of B cells and their terminal differentiation into antibody‐secreting plasma cells. Long‐lived plasma cells (LLPC) may survive for years to decades. Such long‐lived plasma cells are also responsible for producing pathogenic antibodies that cause a variety of challenges such as autoimmunity, allograft rejection, and drug neutralization. Up to now, various therapeutic strategies aimed at durably eliminating pathogenic antibodies have failed, in large part due to their inability to efficiently target LLPCs. Several antibody‐based therapies have recently gained regulatory approval or are in clinical phases of development for the treatment of multiple myeloma, a malignancy of plasma cells. We discuss the exciting potential of using these emerging cancer immunotherapies to solve the antibody problem.

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Section: Car T Cells Targeting Cd19supporting

confidence: 65%

On the road to eliminating long‐lived plasma cells—“are we there yet?”

Markmann

Bhoj

2021

Immunological Reviews

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Section: Discussionmentioning

confidence: 99%

“…However, factors accounting for persistent alloantibody production may include the persistence of cells of donor origin (microchimerism) or the persistence of alloantigens in dendritic cells 30 and the presence of long-lived plasma cells generated during the alloimmune response. [31][32][33] Allosensitization to allografts utilized for repair of heart defects has also been described. [34][35][36] In a study of adults receiving homograft aortic graft implantation, anti-HLA antibodies were shown to persist for up to 15 y.…”

Section: Discussionmentioning

confidence: 99%

Long-term Persistence of Allosensitization After Islet Allograft Failure

et al. 2021

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Background. Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown. Methods. We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter. Results. In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7–15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%–98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects. Conclusions. Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.

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“…The new frontier to oncologic treatments, CAR‐T cells are bioengineered autologous leucocytes encoded using viral vectors to express chimeric antigen receptors, targeting specific tumor cells. Zhang et al 60 . described the case of a 57‐year‐old woman treated with CART‐T cells for a relapsing follicular lymphoma.…”

Section: Future Potential Therapiesmentioning

confidence: 99%

“…Zhang et al. 60 described the case of a 57‐year‐old woman treated with CART‐T cells for a relapsing follicular lymphoma. CAR‐T cells were encoded to recognize cells expressing CD19, inducing a deep and sustained B‐cell depletion, persisting in a follow‐up of two years, and inducing the lymphoma remission.…”

Section: Future Potential Therapiesmentioning

confidence: 99%

Antibody‐mediated rejection after kidney transplantation in children; therapy challenges and future potential treatments

Bertacchi

Parvex

Villard

2022

Clinical Transplantation

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Antibody-mediated rejection (AMR) remains one of the most critical problems in renal transplantation, with a significant impact on patient and graft survival. In the United States, no treatment has received FDA approval jet. Studies about treatments of AMR remain controversial, limited by the absence of a gold standard and the difficulty in creating large, multi-center studies. These limitations emerge even more in pediatric transplantation because of the limited number of pediatric studies and the occasional use of some therapies with unknown and poorly documented side effects. The lack of recommendations and the unsharp definition of different forms of AMR contribute to the challenging management of the therapy by pediatric nephrologists. In an attempt to help clinicians involved in the care of renal transplanted children affected by an AMR, we rely on the latest recommendations of the Transplantation Society (TTS) for the classification and treatment of AMR to describe treatments available today and potential new treatments with a particular focus on the pediatric population.

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Stable HLA antibodies following sustained CD19+ cell depletion implicate a long-lived plasma cell source

Abstract: Key Points HLA-specific alloantibodies can be maintained despite profound CD19+ cell aplasia, likely due to production by CD19− plasma cells.

Cited by 11 publications

References 25 publications

On the road to eliminating long‐lived plasma cells—“are we there yet?”

On the road to eliminating long‐lived plasma cells—“are we there yet?”

Long-term Persistence of Allosensitization After Islet Allograft Failure

Antibody‐mediated rejection after kidney transplantation in children; therapy challenges and future potential treatments

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